ATR Plays a Direct Antiapoptotic Role at Mitochondria, which Is Regulated by Prolyl Isomerase Pin1

• Published in: Molecular cell Vol. 60; no. 1; pp. 35 - 46
• Main Authors: Hilton, Benjamin A., Li, Zhengke, Musich, Phillip R., Wang, Hui, Cartwright, Brian M., Serrano, Moises, Zhou, Xiao Zhen, Lu, Kun Ping, Zou, Yue
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-10-2015
• Subjects: Apoptosis; Ataxia Telangiectasia Mutated Proteins - chemistry; Ataxia Telangiectasia Mutated Proteins - metabolism; bcl-2-Associated X Protein - metabolism; BH3 Interacting Domain Death Agonist Protein - metabolism; Binding Sites; Cell Line, Tumor; Cytochromes c - metabolism; DNA Damage; Gene Expression Regulation; HCT116 Cells; HEK293 Cells; Humans; Mitochondria - genetics; Mitochondria - radiation effects; NIMA-Interacting Peptidylprolyl Isomerase; Peptidylprolyl Isomerase - metabolism; Protein Conformation
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2015.08.008

ATR, a PI3K-like protein kinase, plays a key role in regulating DNA damage responses. Its nuclear checkpoint kinase function is well documented, but little is known about its function outside the nucleus. Here we report that ATR has an antiapoptotic activity at mitochondria in response to UV damage, and this activity is independent of its hallmark checkpoint/kinase activity and partner ATRIP. ATR contains a BH3-like domain that allows ATR-tBid interaction at mitochondria, suppressing cytochrome c release and apoptosis. This mitochondrial activity of ATR is downregulated by Pin1 that isomerizes ATR from cis-isomer to trans-isomer at the phosphorylated Ser428-Pro429 motif. However, UV inactivates Pin1 via DAPK1, stabilizing the pro-survival cis-isomeric ATR. In contrast, nuclear ATR remains in the trans-isoform disregarding UV. This cytoplasmic response of ATR may provide a mechanism for the observed antiapoptotic role of ATR in suppressing carcinogenesis and its inhibition in sensitizing anticancer agents for killing of cancer cells.
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•ATR is a prosurvival protein functioning directly at mitochondria against UV damage•ATR contains a BH3-like domain that allows ATR to act like a Bcl-2 family protein•Mitochondrial ATR is a prolyl cis-isomer regulated by Pin1 versus trans-ATR in nucleus•Mitochondria activity of ATR is independent of its checkpoint kinase activity/ATRIP
DNA damage response regulator ATR is implicated in strategies for cancer prevention and treatment, but the mechanisms remain unclear. Hilton et al. report that besides its hallmark nuclear functions, cytoplasmic ATR is Pin1 regulated, and the cis-isomeric ATR has a direct antiapoptotic role at mitochondria via a BH3 domain after UV damage.